Genomic and transcriptomic features of androgen receptor signaling inhibitor resistance in metastatic castration-resistant prostate cancer.

BACKGROUNDAndrogen receptor signaling inhibitors (ARSIs) have improved outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC), but their clinical benefit is limited by treatment resistance.METHODSTo investigate the mechanisms of ARSI resistance, we analyzed the whole-genome (n = 45) and transcriptome (n = 31) sequencing data generated from paired metastatic biopsies obtained before initiation of first-line ARSI therapy for mCRPC and after radiographic disease progression. We investigated the effects of genetic and pharmacologic modulation of SSTR1 in 22Rv1 cells, a representative mCRPC cell line.RESULTSWe confirmed the predominant role of tumor genetic alterations converging on augmenting androgen receptor (AR) signaling and the increased transcriptional heterogeneity and lineage plasticity during the emergence of ARSI resistance. We further identified amplifications involving a putative enhancer downstream of the AR and transcriptional downregulation of SSTR1, encoding somatostatin receptor 1, in ARSI-resistant tumors. We found that patients with SSTR1-low mCRPC tumors derived less benefit from subsequent ARSI therapy in a retrospective cohort. We showed that SSTR1 was antiproliferative in 22Rv1 cells and that the FDA-approved drug pasireotide suppressed 22Rv1 cell proliferation.CONCLUSIONOur findings expand the knowledge of ARSI resistance and point out actionable next steps, exemplified by potentially targeting SSTR1, to improve patient outcomes.FUNDINGNational Cancer Institute (NCI), NIH; Prostate Cancer Foundation; Conquer Cancer, American Society of Clinical Oncology Foundation; UCSF Benioff Initiative for Prostate Cancer Research; Netherlands Cancer Institute.

Ultrasound combined with FeSO4 facilitated the occurrence of ferroptosis in Vibrio parahaemolyticus.

Ultrasound (US) as a sustainable non-thermal sterilization technology that is employed either independently alone or in combination with other processing methods to eliminate food-borne pathogens in the food industry. In the present study, the synergistic effects of US combined with FeSO4 against Vibrio parahaemolyticus were investigated. The results demonstrated that the combination of ultrasound and FeSO4 had an excellent bactericidal activity on V. parahaemolyticus. Treatment with US (100 W) and FeSO4 (8 µM) for 15 min could kill more than 99.9 % cells. Furthermore, the observed cell death was identified as classical ferroptosis, characterized by ferroptosis hallmarks including iron-dependent, ROS burst, membrane damage and lipid peroxide accumulation. Addition of ferroptosis inhibitor liproxstatin-1 alleviated the cell death induced by the combination treatment. Transcriptome analysis further revealed that the US-FeSO4 treatment significantly influenced pathways related to fatty acid metabolism, ferroptosis, biofilm formation, RNA degradation, oxidative phosphorylation and other key processes, which likely contributed to the occurrence of ferroptosis. Based on these findings, we speculated that cavitation effect of US promoted the entry of Fe2+, leading to the generation of free radicals primarily responsible for ferroptosis by US-FeSO4. Taken together, this study provides valuable insights into the biological pathway involved in ultrasound sterilization and presents an alternative strategy to eradicate microorganism in food products.

T-Box Transcription Factor 2 Mediates Chemoresistance of Endometrial Cancer via Regulating FSP1-involved Ferroptosis.

Chemotherapy is increasingly being used in the first-line treatment of endometrial cancer (EC) patients. However, chemoresistance seriously affects its efficacy. Understanding the underlying molecular mechanisms is critical for EC treatment. We explored the regulatory role of T-Box transcription factor 2 (TBX2)-ferroptosis suppressor protein 1 (FSP1) axis in ferroptosis and chemoresistance of EC. Cisplatin-resistant cell line Ishikawa/DDP cells were utilized to generate TBX2 and FSP1 overexpression and knockdown stable cell lines by using lentivirus infection and puromycin selection. Cell viability and ferroptosis status were evaluated in EC cells with or without Cisplatin and/or FSP1 inhibitor (iFSP1) using CKK-8, lipid peroxidation, malondialdehyde, and lactate dehydrogenase release assays. Endometrial carcinoma xenograft mouse model was established to further explore the function of TBX2-FSP1 axis on ferroptosis and tumor progression in EC. TBX2 suppressed Cisplatin-induced ferroptosis through up-regulating FSP1 expression level in EC cells. On the contrary, knockdown of TBX2 reduced FSP1 expression and significantly promoted Cisplatin-induced ferroptosis. TBX2 or FSP1 overexpression and knockdown promote and inhibit EC tumor growth under Cisplatin treatment, respectively. Interestingly, silence FSP1 could reverse TBX2-mediated ferroptosis inhibition and tumor-promoting effect. TBX2-FSP1 axis inhibits ferroptosis and enhances the Cisplatin resistance, which will provide an important theoretical basis and potential solution for the clinical treatment of EC.

Highly sensitive and selective detection of DCP vapors using pyridine-based fluorescent nanofilms.

A novel fluorescent nanofilm DBAP-ETTA has been developed for diethyl chlorophosphate (DCP) vapor detection with high sensitivity and selectivity. Its smooth, homogeneous structure and large Stokes shift enable significant fluorescence quenching upon DCP exposure. The protonation-based sensing mechanism makes it ideal for real-time, portable DCP vapor sensing.

Cytotoxicity evaluation of organophosphorus flame retardants using electrochemical biosensors and elucidation of associated toxic mechanisms.

In recent years, organophosphorus flame retardants (OPFRs) have been widely used as substitutes for brominated flame retardants with excellent properties, and their initial toxicological effects on the water ecosystem and human health have gradually emerged. However, to date, research on the cytotoxicity and health risks of OPFRs is still limited. Therefore, this study aims to systematically explore the cytotoxic effects and toxic mechanisms of OPFRs on cells. Human liver cancer (HepG2) cells were adopted as an ideal model for toxicity evaluation due to their rapid growth and metabolism. This study proposes a sensitive electrochemical cell-based sensor constructed on a graphitized multi-walled carbon nanotube/ionic liquid/gold nanoparticle-modified electrode. The sensor was used to detect the cytotoxicity of tri(2-butylxyethyl) phosphate (TBEP), tributyl phosphate (TnBP), triphenyl phosphate (TPhP), tri(1,3-dichloro-2-propyl) phosphate (TDCIPP), tri(2-chloropropyl) phosphate (TCPP) and tri(2-chloroethyl) phosphate (TCEP) in the liquid medium, providing insight into their toxicity in water environments. The half-maximal inhibitory concentration (IC50) of TBEP, TnBP, TPhP, TDCIPP, TCPP and TCEP on HepG2 cells were 179.4, 194.9, 219.8, 339.4, 511.8 and 859.0 µM, respectively. Additionally, the cytotoxic mechanism of six OPFRs was discussed from the perspective of oxidative stress and apoptosis, and four indexes were correlated with toxicity. Furthermore, transcriptome sequencing was conducted, followed by a thorough analysis of the obtained sequencing results. This analysis demonstrated a significant enrichment of the p53 and PPAR pathways, both of which are closely associated with oxidative stress and apoptosis. This study presents a simplified and efficient technique for conducting in vitro toxicity studies on organophosphorus flame retardants in a water environment. Moreover, it establishes a scientific foundation for further investigation into the mechanisms of cytotoxicity associated with these compounds.

Molecular and physiological responses of two quinoa genotypes to drought stress.

Quinoa is an important economic food crop. However, quinoa seedlings are susceptible to drought stress, and the molecular mechanism of drought tolerance remains unclear. In this study, we compared transcriptomic and physiological analyses of drought-tolerant (L1) and susceptible (HZ1) genotypes exposed to 20% PEG for 3 and 9 days at seedling stage. Compared with HZ1, drought stress had less damage to photosynthetic system, and the contents of SOD, POD and CAT were higher and the contents of H2O2 and O2 -were lower in L1 leaves. Based on the RNA-seq method, we identified 2423, 11856, 1138 and 3903 (HZ1-C3-VS-T3, HZ1-C9-vs-T9, L1-C3-vs-T3 and L1-C9-vs-T9) annotated DEGs. Go enrichment was shown in terms of Biological Process: DEGs involved in biological processes such as metabolic process, cellular process, and single-organism process were most abundant in all four comparison treatments. In Molecular Function: the molecular functions of catalytic activity, binding and transporter activity have the most DEGs in all four processes. Cellular Component: membrane, membrane part, and cell have the most DEGs in each of the four processes. These DEGs include AP2/ERF, MYB, bHLH, b-ZIP, WRKY, HD-ZIP, NAC, C3h and MADS, which encode transcription factors. In addition, the MAPK pathway, starch and sucrose metabolism, phenylpropanoid biosynthesis and plant hormone signal transduction were significantly induced under drought stress, among them, G-hydrolases-66, G-hydrolases-81, G-hydrolases-78, Su-synthase-02, Su-synthase-04, Su-synthase-06, BRI1-20 and bHLH17 were all downregulated at two drought stress points in two genotypes, PP2C01, PP2C03, PP2C05-PP2C07, PP2C10, F-box01 and F-box02 were upregulated at two drought stress points in two genotypes. These results agree with the physiological responses and RNA-seq results. Collectively, these findings may lead to a better understanding of drought tolerance, and some of the important DEGs detected in this study could be targeted for future research. And our results will provide a comprehensive basis for the molecular network that mediates drought tolerance in quinoa seedlings and promote the breeding of drought-resistant quinoa varieties.

An Atlas of Accessible Chromatin in Advanced Prostate Cancer Reveals the Epigenetic Evolution during Tumor Progression.

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of prostate cancer. mCRPC resists androgen receptor (AR) inhibitors by amplifying AR signaling or by evolving into therapy-resistant subtypes that do not depend on AR. Elucidation of the epigenetic underpinnings of these subtypes could provide important insights into the drivers of therapy resistance. In this study, we produced chromatin accessibility maps linked to the binding of lineage-specific transcription factors (TF) by performing assay for transposase-accessible chromatin sequencing on 70 mCRPC tissue biopsies integrated with transcriptome and whole-genome sequencing. mCRPC had a distinct global chromatin accessibility profile linked to AR function. Analysis of TF occupancy across accessible chromatin revealed 203 TFs associated with mCRPC subtypes. Notably, ZNF263 was identified as a putative prostate cancer TF with a significant impact on gene activity in the double-negative subtype (AR- neuroendocrine-), potentially activating MYC targets. Overall, this analysis of chromatin accessibility in mCRPC provides valuable insights into epigenetic changes that occur during progression to mCRPC. Significance: Integration of a large cohort of transcriptome, whole-genome, and ATAC sequencing characterizes the chromatin accessibility changes in advanced prostate cancer and identifies therapy-resistant prostate cancer subtype-specific transcription factors that modulate oncogenic programs.

Dynamical Attention Hypergraph Convolutional Network for Group Activity Recognition.

Recently, group activity recognition (GAR) has drawn growing interests in video analysis and computer vision communities. The current models of GAR tasks are often impractical in that they suppose that all interactions between actors are pairwise, which only models and leverages part of the information in real entire interactions. Motivated by this, we design a distinct dynamical attention hypergraph convolutional network framework, referred to as DAHGCN, for precise GAR, modeling the entire interactions and capturing the high-order relationships among involved actors in a real-life scenario. Specifically, to learn complementary feature representations for fine-grained GAR, a multilevel feature descriptor (MLFD) module is proposed. Furthermore, for learning higher order interaction relationships, we construct a DAHGCN to accommodate complex group interactions, which can dynamically change the topology of the hypergraph and learn these key representations by virtue of the "similarity-based shared nearest-neighbor (SSNN) clustering" and "attention mechanisms" on hypergraph. Finally, a multiscale temporal convolution (MSTC) module is utilized to explore various long-range temporal dynamic correlations across different frames. In addition, comprehensive experiments on three commonly used GAR datasets clearly demonstrate that, when compared with the state-of-the-art methods, our proposed method can achieve the most optimal performance.

Anthropogenic warming is a key climate indicator of rising urban fire activity in China.

China, one of the most populous countries in the world, has suffered the highest number of natural disaster-related deaths from fire. On local scales, the main causes of urban fires are anthropogenic in nature. Yet, on regional to national scales, little is known about the indicators of large-scale co-varying urban fire activity in China. Here, we present the China Fire History Atlas (CFHA), which is based on 19 947 documentary records and represents fires in urban areas of China over the twentieth century (1901-1994). We found that temperature variability is a key indicator of urban fire activity in China, with warmer temperatures being correlated with more urban fires, and that this fire-temperature relationship is seasonally and regionally explicit. In the early twentieth century, however, the fire-temperature relationship was overruled by war-related fires in large urban areas. We further used the fire-temperature relationship and multiple emissions scenarios to project fire activity across China into the twenty-first century. Our projections show a distinct increase in future urban fire activity and fire-related economic loss. Our findings provide insights into fire-climate relationships in China for densely-populated areas and on policy-relevant time scales and they contribute spatial coverage to efforts to improve global fire models.

The impact of clinical internship experience on nursing students' attitudes towards death and choices of end-of-life care: A self-control study.

AIM: This study aims to explore the impact of emergency department internships on the attitudes towards death among undergraduate nursing students and their preferences for end-of-life care settings. Additionally, the study analyzes the reasons behind nursing students' choices of end-of-life care settings and provides insights for improving undergraduate education on attitudes towards death and end-of-life care, and provide reference for the development of emergency hospice care. DESIGN: This study adopts an observational design with a self-controlled before-and-after approach. METHODS: A questionnaire survey was conducted with 96 nursing interns between July 2021 to June 2022. Demographic information and data on attitudes towards death, and preferences for end-oflife care location were collected by online questionnaire. Paired test were conducted to compare differences between groups. RESULTS: The study included a total of 96 nursing students with an average age of 21.11 years. The scores for the avoidance-acceptance dimension of death attitudes before and after the internship were 2.40 (1.80, 3.00) and 2.20 (1.60, 3.00), respectively, showing a significant difference (Z = -2.084, p = 0.037). Factors such as gender, experience in caring for critically ill or dying patients, knowledge of death education, and discussions about death at home were found to influence nursing students' attitudes towards death. Nursing students expressed a preference for receiving end-of-life care and treatment in their homes or in hospice/palliative care wards, while the intensive care unit, emergency department, and nursing homes were the least preferred settings. There were significant differences in nursing students' preferences for end-of-life care settings before and after the internship (p = 0.000). Importantly, the number of nursing students expressing a desire to receive end-of-life care in the emergency department increased from 2 to 7 after the internship, while the number of students not wanting end-of-life care in the emergency department decreased by 5.

High-Entropy Engineering Reinforced Surface Electronic States and Structural Defects of Hierarchical Metal Oxides@Graphene Fibers toward High-Performance Wearable Supercapacitors.

Construction advanced fibers with high Faradic activity and conductivity are effective to realize high energy density with sufficient redox reactions for fiber-based electrochemical supercapacitors (FESCs), yet it is generally at the sacrifice of kinetics and structural stability. Here, a high-entropy doping strategy is proposed to develop high-energy-density FESCs based on high-entropy doped metal oxide@graphene fiber composite (HE-MO@GF). Due to the synergistic participation of multi-metal elements via high-entropy doping, the HE-MO@GF features abundant oxygen vacancies from introducing various low-valence metal ions, lattice distortions, and optimized electronic structure. Consequently, the HE-MO@GF maintains sufficient active sites, a low diffusion barrier, fast adsorption kinetics, improved electronic conductivity, enhanced structural stability, and Faradaic reversibility. Thereinto, HE-MO@GF presents ultra-large areal capacitance (3673.74 mF cm-2) and excellent rate performance (1446.78 mF cm-2 at 30 mA cm-2) in 6 M KOH electrolyte. The HE-MO@GF-based solid-state FESCs also deliver high energy density (132.85 µWh cm-2), good cycle performance (81.05% of capacity retention after 10,000 cycles), and robust tolerance to sweat erosion and multiple washing, which is woven into the textile to power various wearable devices (e.g., watch, badge and luminous glasses). This high-entropy strategy provides significant guidance for designing innovative fiber materials and highlights the development of next-generation wearable energy devices.

IMT030122, A novel engineered EpCAM/CD3/4-1BB tri-specific antibody, enhances T-cell recruitment and demonstrates anti-tumor activity in mouse models of colorectal cancer.

Colorectal cancer is a major global health burden, with limited efficacy of traditional treatment modalities in improving survival rates. However, recently advances in immunotherapy has improved treatment outcomes for patients with this cancer. To address the continuing need for improved treatment efficacy, this study introduced a novel tri-specific antibody, IMT030122, that targets EpCAM, 4-1BB, and CD3. We evaluated the pharmacological efficacy and mechanism of action of IMT030122 in vitro and in vivo. In in vitro studies, IMT030122 exhibited differential binding to antigens and cells expressing EpCAM, 4-1BB, and CD3. Moreover, IMT030122 relied on EpCAM-targeted activation of intracellular CD3 and 4-1BB signaling and mediated T cell cytotoxicity specific to HCT116 colorectal cancer cells. In vivo, IMT030122 demonstrated potent anti-tumor activity, significantly inhibiting the growth of colon cancer HCT116 and MC38-hEpCAM subcutaneous grafts. Further pharmacological analysis revealed that IMT030122 recruited lymphocytes from peripheral blood into colorectal cancer tissue and exerted durable anti-tumor activity, predominantly by promoting the activation, proliferation, and differentiation of CD8T cells. Notably, IMT030122 still exhibited anti-tumor efficacy even in the presence of significantly depleted lymphocytes in colorectal cancer tissue. The potent pharmacological activity and anti-tumor effects of IMT030122 suggest it may enhance treatment efficacy and substantially extend the survival of patients with colorectal cancer in the future.

HER2 overexpression in urothelial carcinoma with GATA3 and PPARG copy number gains.

HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.

A prostate cancer gastrointestinal transcriptional phenotype may be associated with diminished response to AR-targeted therapy.

Background: Prostate cancer is a heterogenous disease, but once it becomes metastatic it eventually becomes treatment resistant. One mechanism of resistance to AR-targeting therapy is lineage plasticity, where the tumor undergoes a transformation to an AR-indifferent phenotype, most studied in the context of neuroendocrine prostate cancer (NEPC). However, activation of additional de- or trans-differentiation programs, including a gastrointestinal (GI) gene expression program, has been suggested as an alternative method of resistance. In this study, we explored the previously identified GI prostate cancer phenotype (PCa-GI) in a large cohort of metastatic castration-resistant prostate cancer (mCRPC) patient biopsy samples. Methods: We analyzed a dataset of 634 mCRPC samples with batch effect corrected gene expression data from the West Coast Dream Team (WCDT), the East Coast Dream Team (ECDT), the Fred Hutchinson Cancer Research Center (FHCRC) and the Weill Cornell Medical center (WCM). Survival data was available from the WCDT and ECDT cohorts. We calculated a gene expression GI score using the sum of z-scores of genes from a published set of PCa-GI-defining genes (N=38). Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards regression with endpoint overall survival from time of biopsy to death of any cause. Results: We found that the PCa-GI score had a bimodal distribution, identifying a distinct set of tumors with an activated GI expression pattern. Approximately 35% of samples were classified as PCa-GI high, which was concordant with prior reports. Liver metastases had the highest median score but after excluding liver samples, 29% of the remaining samples were still classified as PCa-GI high, suggesting a distinct phenotype not exclusive to liver metastases. No correlation was observed between GI score and proliferation, AR signaling, or NEPC scores. Furthermore, the PCa-GI score was not associated with genomic alterations in AR, FOXA1, RB1, TP53 or PTEN. However, tumors with MYC amplifications showed significantly higher GI scores (p=0.0001). Patients with PCa-GI tumors had a shorter survival (HR=1.5 [1.1-2.1], p=0.02), but this result was not significant after adjusting for the liver as metastatic site (HR=1.2 [0.82-1.7], p=0.35). Patients with PCa-GI low samples had a better outcome after androgen receptor signaling inhibitors (ASI, abiraterone or enzalutamide) than other therapies (HR=0.37 [0.22-0.61], p=0.0001) while the benefit of ASI was smaller and non-significant for PCa-GI high samples (HR=0.55 [0.29-1.1], p=0.07). A differential pathway analysis identified FOXA2 signaling to be upregulated PCa-GI high tumors (FDR = 3.7 × 10-13). Conclusions: The PCa-GI phenotype is prevalent in clinical mCRPC samples and may represent a distinct biological entity. PCa-GI tumors may respond less to ASI and could offer a strategy to study novel therapeutic targets.

Thymol Induces Fenton-Reaction-Dependent Ferroptosis in Vibrio parahemolyticus.

Thymol has efficient bactericidal activity against a variety of pathogenic bacteria, but the bactericidal mechanism against Vibrio parahemolyticus (V. parahemolyticus) has rarely been reported. In the current study, we investigated the bactericidal mechanism of thymol against V. parahemolyticus. The Results revealed that 150 µg/mL of thymol had 99.9% bactericidal activity on V. parahemolyticus. Intracellular bursts of reactive oxygen species (ROS), Fe2+accumulation, lipid peroxidation, and DNA breakage were checked by cell staining. The exogenous addition of H2O2 and catalase promoted and alleviated thymol-induced cell death to a certain extent, respectively, and the addition of the ferroptosis inhibitor Liproxstatin-1 also alleviated thymol-induced cell death, confirming that thymol induced Fenton-reaction-dependent ferroptosis in V. parahemolyticus. Proteomic analysis revealed that relevant proteins involved in ROS production, lipid peroxidation accumulation, and DNA repair were significantly upregulated after thymol treatment. Molecular docking revealed two potential binding sites (amino acids 46H and 42F) between thymol and ferritin, and thymol could promote the release of Fe2+ from ferritin proteins through in vitro interactions analyzed. Therefore, we hypothesized that ferritin as a potential target may mediate thymol-induced ferroptosis in V. parahemolyticus. This study provides new ideas for the development of natural inhibitors for controlling V. parahemolyticus in aquatic products.

Association of complement components with risk of colorectal cancer: A systematic review and meta-analysis.

BACKGROUND: Complement components could contribute to the tumor microenvironment and the systemic immune response. Nevertheless, their role in colorectal cancer (CRC) remains a contentious subject. AIM: To elucidate the relationship between complement components and CRC risk and clinical characteristics. METHODS: Searches were conducted in PubMed, the Cochrane Library, and the China National Knowledge Infrastructure database until June 1, 2023. We included cohort studies encompassing participants aged ≥ 18 years, investigating the association between complement components and CRC. The studies were of moderate quality or above, as determined by the Agency for Healthcare Research and Quality. The meta-analysis employed fixed-effects or random-effects models based on the I² test, utilizing risk ratio (RR) and their corresponding 95% confidence interval (CI) for outcomes. Sensitivity and subgroup analyses were performed to validate the robustness of the collective estimates and identify the source of heterogeneity. RESULTS: Data from 15 studies, comprising 1631 participants that met the inclusion criteria, were included in the meta-analysis. Our findings indicated that protein levels of cluster of differentiation 46 (CD46) (RR = 3.66, 95%CI: 1.75-7.64, P < 0.001), CD59 (RR = 2.86, 95%CI: 1.36-6.01, P = 0.005), and component 1 (C1) (RR = 5.88, 95%CI: 1.75-19.73, P = 0.004) and serum levels of C3 (standardized mean difference = 1.82, 95%CI: 0.06-3.58, P = 0.040) were significantly elevated in patients with CRC compared to healthy controls. Strong expression of CD55 or CD59 was associated with a higher incidence of lymph node metastasis, whereas strong CD46 expression correlated with a higher incidence of tumor differentiation compared to low CD46 expression (P < 0.05 for all). Although specific pooled results demonstrated notable heterogeneity, subgroup analyses pointed to regional differences as the primary source of inconsistency among the studies. CONCLUSION: Our analysis underscores that increased levels of specific complement components are associated with a heightened risk of CRC, emphasizing the potential significance of monitoring elevated complement component levels.

The role of macrophage-derived Exosomes in reversing peritoneal fibrosis: Insights from Astragaloside IV.

BACKGROUND: Peritoneal dialysis (PD) is a successful renal replacement therapy for end-stage renal disease. Long-term PD causes mesothelial-mesenchymal transition (MMT) of peritoneal mesothelial cells (PMCs), leading to peritoneal fibrosis (PF), which reduces the efficiency of PD. Macrophages are thought to play a role in the onset and perpetuation of peritoneal injury. However, the mechanisms by which macrophages-PMCs communication regulates peritoneal fibrosis are not fully understood resulting in a lack of disease-modifying drugs. Astragaloside IV (AS-IV) possessed anti-fibrotic effect towards PF in PD whereas the mechanistic effect of AS-IV in PD is unknown. METHODS: The primary macrophages were extracted and treated with LPS or AS-IV, then co-cultured with primary PMCs in transwell plates. The macrophage-derived exosomes were extracted and purified by differential centrifugation, then co-cultured with primary PMCs. Small RNA-seq was used to detect differential miRNAs in exosomes, and then KEGG analysis and q-PCR were performed for validation. In vivo PD rat models were established by inducing with high-glucose peritoneal dialysis fluid and different concentrations of AS-IV and exosomes were intraperitoneal injection. Through qRT-PCR, western blotting, and luciferase reporting, candidate proteins and pathways were validated in vivo and in vitro. The functions of the validated pathways were further investigated using the mimic or inhibition strategy. PF and inflammatory situations were assessed. RESULTS: We found AS-IV reversed the MMT of PMCs caused by LPS-stimulated macrophages and the improving effect was mediated by macrophage-derived exosomes in vitro. We also demonstrated that AS-IV significantly reduced the MMT of PMCs in vitro or PF in a rat PD model via regulating exosome-contained miR-204-5p which targets Foxc1/ß-catenin signaling pathway. CONCLUSION: AS-IV attenuates macrophage-derived exosomes induced fibrosis in PD through the miR-204-5p/Foxc1 pathway.

Quality Changes and Fungal Microbiota Dynamics in Stored Jujube Fruits: Insights from High-Throughput Sequencing for Food Preservation.

Postharvest rot is an urgent problem affecting the storage of winter jujube. Therefore, the development of new technologies for efficient and safe preservation is very important. This study aimed to elucidate the fungal microbiota found on the epidermis of jujube during the storage period using high-throughput sequencing, as well as to monitor the changes in quality indexes throughout this period. Through internal transcribed spacer (ITS) sequencing, we identified two phyla (Basidiomycota and Ascomycota) and six genera (Cryptococcus, Bulleromyces, Sporidiobolus, Alternaria, Pseudozyma, and Sporobolomyces), which potentially contribute to the spoilage and deterioration of jujube, referred to as "core fungal taxa". A high correlation was further found between preservation indices (including decay rate, firmness, and total soluble solids) and the growth of multiple core fungi over time. These findings will provide insights and a theoretical basis for further research on preservation techniques related to biological control during date fruit storage.

Isobavachalcone induces hepatotoxicity in zebrafish embryos and HepG2 cells via the System Xc--GSH-GPX4 signaling pathway in ferroptosis response.

Isobavachalcone (IBC) is a flavonoid component of the traditional Chinese medicine Psoraleae Fructus, with a range of pharmacological properties. However, IBC causes some hepatotoxicity, and the mechanism of toxicity is unclear. The purpose of this paper was to investigate the possible mechanism of toxicity of IBC on HepG2 cells and zebrafish embryos. The results showed that exposure to IBC increased zebrafish embryo mortality and decreased hatchability. Meanwhile, IBC induced liver injury and increased expression of ALT and AST activity. Further studies showed that IBC caused the increase of ROS and MDA the decrease of CAT, GSH, and GSH-Px; the increase of Fe2+ content; and the changes of ferroptosis related genes (acsl4, gpx4, and xct) and iron storage related genes (tf, fth, and fpn) in zebrafish embryos. Through in vitro verification, it was found that IBC also caused oxidative stress and increased Fe2+ content in HepG2 cells. IBC caused depolarization of mitochondrial membrane potential (MMP) and reduction of mitochondrial ATP, as well as altered expression of ACSl4, SLC7A11, GPX4, and FTH1 proteins. Treatment of HepG2 cells with ferrostatin-1 could reverse the effect of IBC. Targeting the System Xc--GSH-GPX4 pathway of ferroptosis and preventing oxidative stress damage might offer a theoretical foundation for practical therapy and prevention of IBC-induced hepatotoxicity.

Enhancing Built-in Electric Fields via Molecular Symmetry Modulation in Supramolecular Photocatalysts for Highly Efficient Photocatalytic Hydrogen Evolution.

Nature-inspired supramolecular self-assemblies are attractive photocatalysts, but their quantum yields are limited by poor charge separation and transportation. A promising strategy for efficient charge transfer is to enhance the built-in electric field by symmetry breaking. Herein, an unsymmetric protonation, N-heterocyclic π-conjugated anthrazoline-based supramolecular photocatalyst SA-DADK-H+ was developed. The unsymmetric protonation breaks the initial structural symmetry of DADK, resulting in ca. 50-fold increase in the molecular dipole, and facilitates efficient charge separation and transfer within SA-DADK-H+. The protonation process also creates numerous active sites for H2O adsorption, and serves as crucial proton relays, significantly improving the photocatalytic efficiency. Remarkably, SA-DADK-H+ exhibits an outstanding hydrogen evolution rate of 278.2 mmol g-1 h-1 and a remarkable apparent quantum efficiency of 25.1 % at 450 nm, placing it among the state-of-the-art performances in organic semiconductor photocatalysts. Furthermore, the versatility of the unsymmetric protonation approach has been successfully applied to four other photocatalysts, enhancing their photocatalytic performance by 39 to 533 times. These findings highlight the considerable potential of unsymmetric protonation induced symmetry breaking strategy in tailoring supramolecular photocatalysts for efficient solar-to-fuel production.